MicroRNA Regulation of Ionizing Radiation-Induced Premature Senescence

Journal Article · Tue Nov 01 00:00:00 EDT 2011 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2010.09.048· OSTI ID:21590466

Scheiber, Melissa N ^[1]; Neumann, Carola ^[2]; Calin, George A ^[3]; Daohong, Zhou ^[1]

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1. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina (United States)
2. Department of Pharmacology, Medical University of South Carolina, Charleston, South Carolina (United States)
3. Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, Texas (United States)

Purpose: MicroRNAs (miRNAs) have emerged as critical regulators of many cellular pathways. Ionizing radiation (IR) exposure causes DNA damage and induces premature senescence. However, the role of miRNAs in IR-induced senescence has not been well defined. Thus, the purpose of this study was to identify and characterize senescence-associated miRNAs (SA-miRNAs) and to investigate the role of SA-miRNAs in IR-induced senescence. Methods and Materials: In human lung (WI-38) fibroblasts, premature senescence was induced either by IR or busulfan (BU) treatment, and replicative senescence was accomplished by serial passaging. MiRNA microarray were used to identify SA-miRNAs, and real-time reverse transcription (RT)-PCR validated the expression profiles of SA-miRNAs in various senescent cells. The role of SA-miRNAs in IR-induced senescence was characterized by knockdown of miRNA expression, using anti-miRNA oligonucleotides or by miRNA overexpression through the transfection of pre-miRNA mimics. Results: We identified eight SA-miRNAs, four of which were up-regulated (miR-152, -410, -431, and -493) and four which were down-regulated (miR-155, -20a, -25, and -15a), that are differentially expressed in both prematurely senescent (induced by IR or BU) and replicatively senescent WI-38 cells. Validation of the expression of these SA-miRNAs indicated that down-regulation of miR-155, -20a, -25, and -15a is a characteristic miRNA expression signature of cellular senescence. Functional analyses revealed that knockdown of miR-155 or miR-20a, but not miR-25 or miR-15a, markedly enhanced IR-induced senescence, whereas ectopic overexpression of miR-155 or miR-20a significantly inhibited senescence induction. Furthermore, our studies indicate that miR-155 modulates IR-induced senescence by acting downstream of the p53 and p38 mitogen-activated protein kinase (MAPK) pathways and in part via regulating tumor protein 53-induced nuclear protein 1 (TP53INP1) expression. Conclusion: Our results suggest that SA-miRNAs are involved in the regulation of IR-induced senescence, so targeting these miRNAs may be a novel approach for modulating cellular response to radiation exposure.

• OSTI ID: 21590466
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Journal Name: International Journal of Radiation Oncology, Biology and Physics Journal Issue: 3 Vol. 81; ISSN IOBPD3; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
62 RADIOLOGY AND NUCLEAR MEDICINE
ALKYLATING AGENTS
ANIMAL CELLS
BODY
CONNECTIVE TISSUE CELLS
DISEASES
DNA
DNA DAMAGES
FIBROBLASTS
FUNCTIONAL ANALYSIS
GENE AMPLIFICATION
IONIZING RADIATIONS
LAWS
LUNGS
MATHEMATICS
MYLERAN
NEOPLASMS
NUCLEIC ACIDS
OLIGONUCLEOTIDES
ORGANIC COMPOUNDS
ORGANS
POLYMERASE CHAIN REACTION
RADIATIONS
REGULATIONS
RESPIRATORY SYSTEM
RNA
SOMATIC CELLS
TESTING
TRANSCRIPTION
VALIDATION